1. ¹Gene Function Group, Roy Castle Lung Cancer Programme, University of Liverpool Cancer Research Centre, 200 London Road, Liverpool L3 9TA, UK
2. ²Institute of Medical Oncology, University of Bern, 3010 Bern, Switzerland
3. ³Human Genomics Research Group, Institute for Science and Technology in Medicine, Keele University School of Medicine, Stoke-on-Trent, UK
4. ⁴Christie Hospital NHS Trust, Manchester, UK
5. ⁵Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK

Correspondence: Dr J Heighway, Current address: Cancer Communications, Suite 2, 59-63 Station Road, Northwich, Cheshire CW9 5LT, UK; E-mail: jim@heighway.net

⁶These authors contributed equally to this work

Received 11 April 2005; Revised 20 July 2005; Accepted 11 August 2005.

Abstract

Aurora kinases are key regulators of chromosome segregation during mitosis. We have previously shown by microarray analysis of primary lung carcinomas and matched normal tissue that AURKB (22 out of 37) and AURKA (15 out of 37) transcripts are frequently over-represented in these tumours. We now confirm these observations in a second series of 44 carcinomas and also show that aurora B kinase protein levels are raised in the tumours compared to normal tissue. Elevated levels of expression in tumours are not a consequence of high-level amplification of the AURKB gene. Using a coding sequence polymorphism we show that in most cases (seven out of nine) tumour expression is predominantly driven from one AURKB allele. Given the function of aurora B kinase, we examined whether there was an association between expression levels and genetic instability. We defined two groups of high and low AURKB expression. Using a panel of 10 microsatellite markers, we found that the group showing the higher level of expression had a higher frequency of allelic imbalance (P=0.0012). Analysis of a number of other genes that are strongly and specifically expressed in tumour over normal lung, including SERPINB5, TERT and PRAME, showed marked allelic expression imbalances in the tumour tissue in the context of balanced or only marginally imbalanced relative allelic copy numbers. Our data support a model of early carcinogenesis wherein defects in the process of inactivation of lung stem-cell associated genes during differentiation, contributes to the development of carcinogenesis.